This invention relates to the total synthesis of certain 1-carbapenems and their pharmaceutically acceptable salt, ester and amide derivatives which are useful as antibiotics. Such compounds may generically be represented by the following structural formula (I): ##STR2## wherein R.sup.6, R.sup.7, and R.sup.8 are independently selected from the group consisting of hydrogen, substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: ##STR3## wherein, relative to the above listed substituents on R.sup.6, R.sup.7, and R.sup.8, the groups R.sup.1 and R.sup.2 are independently selected from: hydrogen, alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulphur atoms and wherein the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms.
This invention also relates to the carboxyl derivatives of I which are antibiotics and which may be represented by the following generic structure (I): ##STR4## wherein X' is oxygen, sulphur or NR' (R'=H or lower alkyl having 1-6 carbon atoms); and R.sup.3 ' is, inter alia, representatively selected from the group consisting of hydrogen, conventional blocking groups such as trialkylsilyl, acyl and the pharmaceutically acceptable salt, ester and amide moieties known in the bicyclic .beta.-lactam antibiotic art; the definition of R.sup.3 ' is given in greater detail below.
Starting from L-aspartic acid, the process proceeds via intermediates II, III, IV and V: ##STR5## wherein: R.sup.6 and R.sup.7 are previously defined; X is a conventional leaving group and R.sup.2' is hydrogen, a pharmaceutically acceptable ester moiety or a conventional, readily removable protecting group or salt cation. For intermediates IV, R.sup.2' is as defined but preferably is an ester moiety defined under R.sup.2'. R.sup.1' is hydrogen or a readily removable protecting group such as a triorganosilyl group. R.sup.a, R.sup.b and R.sup.c are independently selected from alkyl, aryl and aralkyl. The details of the total synthesis are given below.
The final compounds prepared by the process of this invention are disclosed and claimed in the following co-pending, commonly assigned U.S. patent application Ser. No. 843,375 abandoned filed Oct. 19, 1977; U.S. patent application Ser. No. 933,681 abandoned filed Aug. 17, 1978; U.S. patent application Ser. No. 31,694 filed Apr. 19, 1979 and in concurrently filed U.S. patent application Ser. Nos. 134,604 filed Mar. 27, 1980; 129,851, filed Mar. 27, 1980 abandoned; 134,381, filed Mar. 27, 1980 and now abandoned. To the extent that the foregoing U.S. Patent Applications describe the antibiotic utility of final compounds I and to the extent that they define substituents R.sup.6, R.sup.7, R.sup.8, R', X' and R.sup.3' they are hereby incorporated by reference.
Thus, it is an object of the present invention to provide a novel class of antibiotics which are useful in animal and human therapy and in inanimate systems. These antibiotics are active against a broad range of pathogens which representatively include both gram positive bacteria such as S. aureus, Strep. pyogenes, and B. subtilis, and gram negative bacteria such as E. coli, Pseudomonas, Proteus morganii, Serratia, and Klebsiella. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their non-toxic pharmaceutically acceptable salts; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated.